The liver is the largest organ in human body and fulfills the most important functions such as metabolism and storage of nutritional substances, detoxicating various substances, etc. The liver maintains circulatory dynamics under normal conditions as a circulatory system next to systemic circulation and pulmonary circulation. Therefore, when hepatic cells are adversely affected either acutely or chronically by causes such as toxic substances, drugs, alcohol, viruses, etc. passing through the liver or by malnutrition, radiation, cholestasia, etc., the entire body is adversely affected.
In liver disorder, characteristic changes are observed from clinical, biochemical and histological viewpoints.
Liver disorder is characterized by increase of hepatic enzymes such as glutamic pyruvic transaminase ("GPT"), glutamic oxaloacetic transaminase ("GOT"), alkaline phosphatase ("AL-P"), sorbitol dehydrogenase ("SDH"), etc. in blood or by increase of serum bilirubin.
Measurements of activity of hepatic enzyme and bilirubin value in blood are utilized for characterization and judgment of degrees of liver disorder, and these methods are generally used for clinical examination. For example, increase of serum AL-P activity suggests physical blocking of extrahepatic bile duct, early development of liver cirrhosis or arrest of choleresis by drug. Increases of activity of serum GPT, GOT and SDH are common to all types of liver disorder and indicate damage of hepatic cells (Merk Manual, 13th edition, Chapter 8, p. 836, 1977).
Liver disorder is associated with necrosis of hepatic cells, and this necrosis is histologically identifiable and provides excellent indices to show degree of liver disorder.
Since the degree of liver disorder can be judged by conditions of hepatic enzymes in blood, serum bilirubin and necrosis of hepatic cells, these indices are generally used in search of preventive and therapeutic agents against liver disorder. Various models of hepatitis have been developed for experimental evaluation of hepatic disorder. Of these models, the liver disorder caused by hepatic toxicants such as D-galactosamine, carbon tetrachloride, etc. are most akin to the viral hepatitis or the hepatitis caused by drug, toxicants, etc. as actually seen.
In the hepatic disorder caused by carbon tetrachloride, the linkage of carbon tetrachloride is severed in liver by cytochrome P-450, thereby generating the highly toxic free radical (.CCl.sub.3), and it is generally believed that this free radical causes the disorder by combining with thiol group of protein in hepatic cell membrane or by accelerating peroxidation reaction of the lipids in cell membrane. (Biochem. pharmacol., Vol. 25, p. 2163, 1976, and Biochem. pharmacol., Vol. 21, p. 49, 1972). As the result, it biochemically induces suppression of protein synthesis in liver and escape of hepatic enzymes such as GPT, GOT and SDH into blood. Histologically, it causes coagulation necrosis, edematous degeneration and fat formation, etc.
It is said that the models with disorder caused by carbon tetrachloride and D-galactosamine are akin to the liver disorder due to chronic alcoholism. On the models with carbon tetrachloride, various descriptions have been given in literature: Amer. J. Path., Vol. 79, p. 579, 1975; Virchowa Arch, B. Cell. Path., Vol. 26, p. 331, 1978; and Semirars in Liver Disease, Vol. 1, p. 143, 1981. It is described that this model is most akin to the liver disorder caused by viruses, drugs, toxicants, etc.
As liver disorders, there are acute hepatitis, chronic hepatitis, liver cirrhosis, fatty liver, etc., and the causes are diverse such as toxicants, drugs, alcohol, viruses, malnutrition, radiation, cholestasia, etc. Various preventive and therapeutic agents have been conceived against these liver disorders. Most of these drugs were the drugs to prevent and treat the metabolic anomaly, which secondarily occurs when hepatic cells are affected, and they are disadvantageous in that the therapeutic effects against liver disorders caused by specific causes such as viruses are rather weak.
The present invention offers preventative and therapeutic agents against various types of liver disorders.